The objective of our research focuses on the continued characterization of mutations and altered expression patterns of cyclin-dependent kinase inhibitors (CKI) as they rate to processes of tumorigenesis and tumor progression in prostate cancer. It is our hypothesis that abnormalities of KIP and INK genes, as well as those that affect their encoded products, produce a selective advantage for prostate growth and an aggressive behavior in prostate cancer patients. The Specific Aims are outlined as follows: Aim #1: To determine the frequency and potential clinical relevance of mutations affecting the KIP genes, as well as altered patterns of expression of their encoded proteins, in benign prostatic hyperplasia (BPH) and prostate carcinoma. We have found distinct p27 anomalies in BPH and prostate tumors, supporting the postulate that BPH is not a premalignant lesion. Moreover, prostatic carcinomas displaying a p27 negative phenotype were found to be biologically more aggressive. We plan to validate these observations and to study p21 and p57 genes. Aim #2: To define the rate and possible clinical relevance of mutations arising in the INK genes, as well as altered patterns of expression of their encoded products, in BPH and prostatic carcinoma. Preliminary data reveals that altered patterns of p16 expression and methylation of he p16 promoter are frequent events in prostate cancer. We plan to extend and validate these data and to assess the relevance of alterations affecting p18 and p19. Aim #3: To further characterize the histopathology of prostatic tissue in animal models for loss of KIP or INK function, and to produce transgenic models using tissue-specific promoters. We have engineered CKI knockout mice (ie, p27 and Ink4a). p27 mull mice develop hyper-cellular prostatic glands; however,over prostate neoplasms are not observed. Transgenic mice will be generated using cyclins E or each D-type fused to the rat probasin promoter in the presence and absence of either p27 or p16. A model mimicking the human disease is expected. The goal is to translated basic and clinical research findings into clinical studies, and to collaborate with the O'Brien Centers and members of the scientific community, evaluating tumor markers of potential relevance.